Pharmaceutical preparations for the treatment of hypertonia

ABSTRACT

Pharmaceutical preparations containing a combination of the antihypertensively active amino acid and of a Beta -hydroxylase inhibitor for the treatment of hypertonia. Said preparations prolong the antihypertensive action substantially greater than that would be achieved by administration of individual compounds.

United States Patent [191 Hedwall [451 May 13, 1975 PHARMACEUTICALPREPARATIONS FOR THE TREATMENT OF HYPERTONIA [75] Inventor: PhyllisRoberta Hedwall, Basel,

Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

{22] Filed: Oct. 30, 1972 [2!] Appl. No.: 302,156

[30] Foreign Application Priority Data Nov, 11, 1971 Switzerlandl6377/7l Sept, l5, I972 Switzerland 13545/72 [52] US. Cl 424/263;424/319 [51] Int. Cl A6lk 27/00 [58] Field oi Search 424/263, 319

[5 6] References Cited OTHER PUBLICATIONS lkuko et al.-Chem. Abst. Vol.75, (l97l), page Branislav et al.-Chem. Abst Vol. 74, (1971), page97833n.

Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Joseph G. Kolodny;John J. Maitner [57] ABSTRACT 10 Claims, No Drawings 1 PHARMACEUTICALPREPARATIONS FOR THE TREATMENT OF HYPERTONIA The invention relates tonew pharmaceutical preparations for the treatment of hypertonia. Thesenew pharmaceutical preparations contain a combination of ananti-hypertensively active aminoacid and a B-hydroxylase inhibitor.

Anti-hypertensively active aminoacids are above all compounds of thetype of a-methyldopa.

Anti-hypertensively active aminoacids, above all compounds of the typeof a-methyldopa, especially a-methyldopa itself, have proved successfulin the therapy of hypertonia. Thus, a-methyldopa is used successfully inpractically all forms of hypertonia, at a dosage of about 0.5 g to about2 g, and at times even up to about 4 g, per day, compare E. Mutschler,Arzneimib telwirkungen (Effects of Medicines), Wissenschaft licheVerlagsgesellschaft, mbH, Stuttgart l970, page 134.

B Hydroxylase inhibitors, for example bis- (diethylthiocarbamoyl)-disulphide, bis-{(3-aza-3- methyl-hexylene-l ,6)-thiocarbamoyl]-disulphide and above all compounds of the type of fusaric acid,especially fusaric acid and its salts, such as its calcium salt, havealso proved very successful in the therapy of hypertonia, compare .lap.Circ. J. 35, 339 (l97l).

It has now been found, surprisingly that by treatment of hypertonia witha combination of an antihypertensively active aminoacid and aB-hydroxylase inhibitor the antihypertensive action can be prolonged andbe rendered more even and the dosage of the components, that is to sayof the antihypertensively active aminoacid and of the ,B-hydroxylaseinhibitor, can be reduced, as can be shown by Goldblatts method on male,renal hypertonic rats on administration of customary doses of thecomponents orally or subcutaneously. The prolongation of theanti-hypertensive action here proves to be substantially greater thanwould correspond to the sum of the anti-hypertensive action of theactive substance components.

This prolongation of the anti-hypertensive action makes it possible tomanage with a single daily administration of the combination preparationaccording to the invention. The substantially more even action in lowering the blood pressure considerably reduces the disad vantages of afluctuation in blood pressure in the course of the day, such as occursin the known treatment of hypertonia by means of the individual activesubstance components, and makes the therapy more balanced and moreeasily tolerated from the point of view of the patients. The reductionin the component dosages reduces the dangers of an overdosage and is ofadvantage especially because of the known high doses of theanti-hypertensively active aminoacids, especially of the compounds ofthe type of wmethyldopa, so that a general reduction in the strain onthe organism of the patient is achievable.

Possible compounds of the type of a-methyldopa are above allor-amino-a-methyl-B-hydroxyphenylpropionic acids, their salts andesters.

Salts are especially salts with bases, such as alkali metal carbonates,for example sodium carbonate or potassium carbonate, alkali metalbicarbonates, alkali metal hydroxides, such as sodium hydroxide orpotassium hydroxide, or corresponding alkaline earth metal compounds,such as those of calcium or magnesium, or

ammonia, as well as amines, such as aliphatic amines, for example loweralkylamines, such as trimethylamine or triethylamine, and also aluminiumcompounds, such as aluminium hydroxide, for example salts of two mols ofacid and one mol of aluminium hydroxide which are suitable especiallybecause of their slower resorption, lack of odour and lowgastro-intestinal disturbances.

Esters are above all lower alkyl esters, such as methyl esters and ethylesters. Lower radicals are, in the preceding and following texts, aboveall those with up to 7, preferably with up to 4, C atoms.

Compounds to be singled out particularly area-amin0-a-methyl-B-(4-hydroxyphenyl)-propionic acid and veryparticularly a-amino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid,which is known by the name of a-methyldopa, as well as their salts, suchas, in particular, their alkali metal salts or alkaline earth metalsalts, and secondly their esters, such as lower alkyl esters.

B-Hydroxylase inhibitors are, for example, bis- (diethylthiocarbamoyl)-disulphide, bis-[ 3-aza-3-methyl-hexylene-l,6)-thiocarbamoyl]-disulphide and especially compoundsof the type of fusaric acid.

Possible compounds of the type of fusaric acid are above all those ofthe formula I wherein R is an esterified or amidised carboxyl group butabove all a free carboxyl group and R is an alkyl group, and theirsalts.

An esterified carboxyl group is, for example, a carboxyl group which isesterified with a lower alkanol, with the lower alkanol in particularhaving up to 8, preferably up to 4, C atoms and being branched, orpreferably, straight-chain in the alkyl part. As examples of anesterified carboxyl group there may be mentioned: n-butoxycarbonyl,n-propoxycarbonyl, ipropoxycarbonyl and in particulalr ethoxycarbonyland very especially methoxycarbonyl.

An amidised carboxyl group is, for example, a N- monosubstituted orN-disubstituted carbamoyl group and very particularly theN-unsubstituted carbamoyl group. As substituents there may be mentioned:lower alkyl, especially with up to 8 C atoms, such as branched or, inparticular, straightchain lower alkyl with, in particular, up to 4 Catoms, for example n-butyl, n-propyl, i-propyl and especially ethyl andvery particularly methyl.

An alkyl group R is, in particular, a branched or above all astraight-chain alkyl group with up to 9 C atoms, preferably n-pentyl andvery particularly nbutyl.

Salts are especially salts with bases, such as those mentioned above,above all alkali metal salts and alkaline earth metal salts, and veryparticularly the calcium salt.

Depending on the number of their asymmetric carbon atoms the activesubstances mentioned can be present in the form of isomer mixtures, pureisomers (racemates) or optical antipodes. Preferably they are in eachcase used in the form of the more active or less toxic isomer orantipode. For example, as a-methyldopa its laevo-rotatory antipode canpreferably be used.

Active substances with basic groups, especially esters of the type ofa-methyldopa, can be present in the free form or in the form of theirnon-toxic salts. Possible salts of this nature are especially salts withorganic or inorganic acids. such as hydrogen halide acids, sulphuricacid, phosphoric acid, nitric acid, perchloric acid, aliphatic,alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic acids,such as formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid;phenylacetic, benzoic, p-aminobenzoic, anthranilic, phydroxybenzoic,salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic,ethanesulphonic, hydroxyethanesulphonic and ethylenesulphonic acid;halogenobenzenesulphonic, toluenesulphonic and naphthalenesulphonic acidor sulphanilic acid; cyclohexyl-sulphamic acid, methionine, tryptophane,lysine or arginine.

The invention relates both to pharmaceutical prepa rations containing acombination of an antihypertensively active aminoacid, especially onementioned above as being preferred, and a B-hydroxylase inhibitor,especially one mentioned above as being preferred, and to themanufacture of such preparations as well as the use of the activecompounds in the form of the said preparations, or by combined butseparate administration, for the treatment of hypertonia.

Pharmaceutical preparations to be particularly singled out contain, asthe anti-hypertensively active aminoacid,a-aminoa-methyl-B-(4-hydroxyphenyl)- propionic acid oror-amino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid or a salt or alower alkyl ester thereof, and as the B-hydroxylase inhibitor, acompound of the formula I] wherein R, is lower alkoxycarbonyl, carbamoylor carboxyl and R is alkyl with 3-6 C atoms, or a salt thereof.

Suitable preparations are, in particular, also those which contain, asthe anti-hypertensively active aminoacid, oz-methyl-p-tyrosine or a saltthereof, and, as the B-hydroxylase inhibitor, a compound of the formulall 4 Very particularly preferred pharmaceutical preparations arethose which contain, as the anti hypertensively active aminoacid,a-amino-a-methyhfi- 3,4-dihydroxyphenyl)-propionic acid (a-methyldopa),or the methyl ester, ethyl ester or a salt thereof, ora-methyl-p-tyrosine, and, as the B-hydroxylase inhibitor,5-n-pentylpicolinic acid or preferably 5-nbutylpicolinic acid (fusaricacid), or the methyl ester, ethyl ester or a sait thereof, orbis-(diethylthiocarbamoyl)-disulphide or bis-l(3-aza-3-methyl-hexylene-1,6 )-thiocarbamoyl l-disulphide.

The invention above all, however, relates to pharmaceutical preparationscontaining a-aminoa-methyl-/3- (3,4-dihydroxyphenyl)propionic acid or anontoxic salt thereof and S-n-butyl-picolinic acid or a nontoxic saltthereof.

Accordingly, the use of these preferred preparations or the use of theindividual components in a combination therapy is also a particularsubject of the invention.

In the new preparations, the ratio of the antihypertensively activeaminoacid to the B-hydroxylase inhibitor can vary within considerablelimits.

The dosage of the new preparations depends on the effectiveness of theactive substance components concerned and on the individual requirementsof the patient. Using the preparations according to the invention thedaily dosage of the active substance components can generally be reducedto between about half and one-third of the customary separate dailydosage.

Thus, for example, the abovernentioned preparations which haveparticularly been singled out can contain about -200 mg, especially -200mg, of 0ramino-a-methyl-fi-( 3,4-dihdyroxyphenyl)-propionic acid andabout 50-200 mg, especially 100-200 mg, of the calcium salt of5-n-butylpicolinic acid.

The preferred preparations can, however, also contain about 100-200 mg,especially 150-200 mg, ofmamino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid and about 40-150mg, especiaily 60-l00 mg, of bis-( diethylthiocarbamoyl)-disulphide orbis-[( 3-aza-3- methyl-hexylenel ,6 )-thiocarbamoyl l-disulphide.

The daily dosage is about 1-6 such individual dosages, which arepreferably administered all at once.

The pharmaceutical preparations according to the invention areprincipally suited to oral or parenteral administration and arepreferably in the form ofa mixture with a pharmaceutical, organic orinorganic, solid or liquid excipient which is suitable, for example, forenteral or parenteral administraton. Possible substances for forming theexcipient are those which do not react with the active substances suchfor example, water, gclatine, lactose, starch. stearyl alcohol,magnesium stearate, talc, vegetable oils, benzyi alcohols, gum,propylene glycols, white petroleum jelly or other known medicinalexcipients, The pharmaceutical preparations can, for example. be in theform of tablets, dragees, capsules or suppositories or in a liquid formas solutions (for example as an elixir or syrup), suspensions oremulsions. They are optionally sterilised andfor contain auxiliariessuch as preservatives, stabilisers, wetting agents or emulsifiers,solubilising agents or salts for regulating the osmotic pressure orbuffers. They can also contain other therapeutically valuablesubstances. The pharmaceutical preparations are forrnuiated inaccordance with customary methods.

The anti-hypertensively active aminoacids employed, and theB-hydroxylase inhibitors, are known.

The invention is explained with the aid of the exam ples which followwithout thereby in any way intending to restrict the scope of theinvention.

EXAMPLE 1 Tablets containing 200 mg of oz-methyldopa and 300 mg of thecalcium salt of fusaric acid:

Composition aMcthyldopa 200 mg Calcium salt of fusaric acid 300 mgLactose 4] mg Wheat starch 75 mg Colloidal silica 16 mg Talc l6 mgMagnesium stearate 2 mg Manufacture The a-methyldopa and the calciumsalt of fusaric acid are mixed with the lactose, a part of the wheatstarch and with colloidal silica and the mixture is forced through asieve. A further part of the wheat starch is worked into a paste with a5-fold amount of water on a water bath and the powder mixture is kneadedwith this paste until a slightly plastic mass has been produced.

The plastic mass is forced through a sieve of approx. 3 mm mesh widthand dried and the dry granules are again forced through a sieve.Thereafter the residual wheat starch, talc and magnesium stearate aremixed in and the resulting mixture is pressed to give tablets weighing650 mg (having a breaking groove).

EXAMPLE 2 Tablets containing the following active substances aremanufactured analogously to Example l:

mMcthyldopu Bis-l dicthylthiocarbamoyl )-disulphidc EXAMPLE 3 Tabletscontaining the following active substances are manufactured analogouslyto Example I:

mMethyldopa 200 mg Bis-H 3-azz|-3-mcthyl-hcxylenc l .6)-thioeurhamoyll-disulphinlc 80 mg I R1 wherein R is an esterified, amidised or freecarboxyl group and R is an alkyl group, a non-toxic salt thereof,bis-(diethylthiocarbamoyl)-clisulphide and bis-[(3-aza-3-methylhexylene-l ,6)-thiocarbamoyl ]-disulphide.

2. The pharmaceutical preparation of claim 1, containing an effectiveamount of a compound selected from the group consisting ofa-aminoa-methylB-M- hydroxyphenyl)propionic acid, a-amino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid and nontoxic salts thereof and aneffective amount of a B-hydroxylase inhibitor selected from the groupconsisting of fusaric acid, bis-(diethylthiocarbamoyD-disulphide andbis-[(3-aza-3-methyl-hexylene-l,6)-thiocarbamoyl]-disulphide.

3. The pharmaceutical preparation of claim 1, which contains aneffective amount of a compound selected from the group consisting ofa-amino-a-methyl-B-(4- hydroxyphenyl)-propionic acid,a-amino-a-methyl-B- (3,4-dihydroxyphenyl)-propionic acid, the alkalimetal salts and alkaline earth metal salt thereof and an effectiveamount of a compound selected from the group consisting ofS-n-pentyl-picolinic acid, 5-nbutyl-picolinic acid, methyl and ethylesters thereof and nontoxic salt thereof.

4. The pharmaceutical preparation of claim 1, which contains aneffective amount of a compound selected from the group consisting ofa-amino-a-methyl-B-(3,4- dihydroxyphenyll-propionic acid, non-toxicalkali metal salts thereof and non-toxic alkaline earth metal saltsthereof and an effective amount of a compound selected from the groupconsisting of S-n-butylpicolinic acid, its methyl or ethyl ester, and anon toxic salt thereof.

5. The pharmaceutical preparation of claim 1, which containsa-amino-a-methyl-B-(3,4-dihydroxyphenyl)- propionic acid or a non-toxicsalt thereof and 5-nbutyl-picolinic acid or a nontoxic salt thereof.

6. The pharmaceutical preparation of claim 1, which contains effectiveamounts of a-amino-a-methyl-B- (3,4-dihydroxyphenyl)-propionic acid or anon-toxic salt thereof, and bis-(diethylthiocarbamoyl)- disulphide.

7. The pharmaceutical preparation of claim I, which contains effectiveamounts of a-amino-oz-methyl-B- (3,4'dihydroxyphenyl)-propionic acid ora non-toxic salt thereof, and bis-[(3-aza-3-methyl-hexylene-l,6)-thiocarbamoyl]-disulphide.

8. The pharmaceutical preparation of claim 1, containing l00200 mg ofa-amino-a-methyLB-(BA- dihydroxyphenyl)-propionic acid and 50-200 mg ofthe calcium salt of S-n-butylpicolinic acid.

9. The pharmaceutical preparation of claim 1, containing -200 mg ofa-amino-amethyl-B-UA- dihydroxyphenyl)-propionic acid and l00-200 mg ofthe calcium salt of S-n-butylpicolinic acid.

10. Process for the treatment of hypertonia, characterized in that apharmaceutical preparation of claim 1 is administered to a warm-bloodedorganism.

1. A PHARMACEUTICAL PREPARATION FOR TREATING HYERTONIA WHICH CONTAINS ANEFFECTIVE AMOUNT OF AN EFFECTIVE AMOUNT OF AN A AMINO ACID COMPOUNDSELECTED FROM THE GROUP CONSISTING OF ANA-AMINO-A-METHYL-B-(HYDROXYLATED HENYL)-PROPIONIC ACID, A NON-TOXIC SALTTHEREOF AND A LOWER ALKYL ESTER THEREOF, AND AN EFFECTIVE AMOUNT OF AB-HYDROXYLASE INHIBITOR COMPOUND SELECTED FROM THE GROUP CONSISTING OF ACOMPOUND OF THE FORMULA
 2. The pharmaceutical preparation of claim 1,containing an effective amount of a compound selected from the groupconsisting of Alpha -amino Alpha -methyl- Beta-(4-hydroxyphenyl)-propionic acid, Alpha -amino- Alpha -methyl- Beta-(3,4-dihydroxyphenyl)-propionic acid and nontoxic salts thereof and aneffective amount of a Beta -hydroxylase inhibitor selected from thegroup consisting of a compound of fusaric acid,bis-(diethylthiocarbamoyl)-disulphide andbis-((3-aza-3-methyl-hexylene-1,6)-thiocarbamoyl)-disulphide.
 3. Thepharmaceutical preparation of claim 1, which contains an effectiveamount of a compound selected from the group consisting of Alpha -amino-Alpha -methyl- Beta -(4-hydroxyphenyl)-propionic acid, Alpha -amino-Alpha -methyl- Beta -(3,4-dihydroxyphenyl)-propionic acid, its alkalimetal salt and an alkaline earth metal salt thereof and an effectiveamount of a compound selected from the group consisting of5-n-pentyl-picolinic acid, 5-n-butyl-picolinic acid, methyl and ethylesters thereof and non-toxic salt thereof.
 4. The pharmaceuticalpreparation of claim 1, which contains an effective amount of a compoundselected from the group consisting of Alpha -amino- Alpha -methyl- Beta-(3,4-dihydroxyphenyl)-propionic acid, non-toxic alkali metal saltsthereof and non-toxic alkaline earth metal salts thereof and aneffective amount of the compound selected from the group consisting of5-n-butyl-picolinic acid, its methyl or ethyl ester, and a non-toxicsalt thereof.
 5. The pharmaceutical preparation of claim 1, whichcontains Alpha -amino- Alpha -methyl- Beta-(3,4-dihydroxyphenyl)-propionic acid or a non-toxic salt thereof and5-n-butyl-picolinic acid or a nontoxic salt thereof.
 6. Thepharmaceutical preparation of claim 1, which contains effective amountsof Alpha -amino- Alpha -methyl- Beta -(3,4-dihydroxyphenyl)-propionicacid or a non-toxic salt thereof, andbis-(diethylthiocarbamoyl)-disulphide.
 7. The pharmaceutical preparationof claim 1, which contains effective amounts of Alpha -amino- Alpha-methyl- Beta -(3,4-dihydroxyphenyl)-propionic acid or a non-toxic saltthereof, andbis-((3-aza-3-methyl-hexylene-1,6)-thiocarbamoyl)-disulphide.
 8. Thepharmaceutical preparation of claim 1, containing 100-200 mg of Alpha-amino- Alpha -methyl- Beta -(3,4-dihydroxyphenyl)-propionic acid and50-200 mg of the calcium salt of 5-n-butylpicolinic acid.
 9. Thepharmaceutical preparation of claim 1, containing 150-200 mg of Alpha-amino- Alpha -methyl- Beta -(3,4-dihydroxyphenyl)-propionic acid and100-200 mg of the calcium salt of 5-n-butylpicolinic acid.
 10. Processfor the treatment of hypertonia, characterized in that a pharmaceuticalpreparation of claim 1 is administered to a warm-blooded organism.